Abstract

Budd-Chiari Syndrome (BCS) is a group of disorders resulting from obstruction to hepatic venous outflow; myeloproliferative disorder (MPD) accounts for 10–40% of cases. A number of BCS cases labelled as ‘idiopathic’ do not fulfil the accepted diagnostic criteria for MPD but have features suggestive of a latent form of MPD based on hyperplastic bone marrow and spontaneous erythroid colony progenitor cell culture studies; these cases may subsequently develop overt MPD. A clonal mutation in JAK2 tyrosine kinase (JAK2V617F) occurs in a high proportion of patients with MPD and is of potential use in the characterization of latent MPD in BCS. We studied 44 patients with BCS (female n=27, mean age 36.1 years, SD 13) presenting between 1985 and 2005. Genomic DNA obtained from archived bone marrow films was screened by allele-specific PCR for the JAK2V617F tyrosine kinase mutation. JAK2V617F was detected in 27/44 (61.4%) subjects. Fulminant hepatic failure was the presenting feature in 86.4%. 3/38 subjects had previously diagnosed Polycythemia Vera and all of these were JAK2V617F positive. Analysis for hereditary thrombophilia in 32/44 cases showed Factor V Leiden (FVL) heterozygosity (n=2) and Protein C deficiency (n=1); JAK2V617F was detected in one of the FVL cases. Screening for antiphospholipid antibodies and paroxysmal nocturnal hemoglobinuria in 31 and 30 out of 44 cases respectively proved negative. 22/44 cases had splenomegaly of which 72.2% had JAK2V617F detected. Mean hemoglobin concentration was higher in patients with JAK2V617F (12.4 g/dL, SD 2.8) compared to the wild-type allele (10.2 g/dL, SD 2.1)(p=0.005). Mean neutrophil count was similar (p=0.26) in both groups (JAK2V617F 7.8 x109/L, SD 5.5; wild-type 6.1 x109/L, SD 4.5). Mean platelet count was higher (p=0.01) in subjects with JAK2V617F (289 x109/L, SD 192) compared to wild-type (180 x109/L, SD 158). The bone marrow (BM) was hyperplastic in all lineages in 19/44 subjects of which 15 (78.9%) contained the JAK2V617F mutation. Importantly, in 25/44 subjects without hyperplastic BM, 48% had JAK2V617F detected. Clonal cytogenetic abnormalities occurred in 6/44 subjects all of which carried JAK2V617F. In 35 evaluable subjects, 10/35 (28.6%) showed endogenous erythroid colony (EEC) formation (8/10 JAK2V617F positive), and the remainder (25/35) showed no EEC formation (14/25 JAK2V617F positive). Treatment of BCS included anticoagulation (n=44), porto-systemic shunt insertion (n=26) and orthotopic liver transplantation (OLT) (n=15). Overall survival was 81.8% (median 32.5 months, range 2 days-240 months). In the 8 non-survivors, JAK2V617F was detected in 50%. 15/44 subjects underwent OLT (11/15 JAK2V617F positive) of which 14/15 are alive at a median of 36 months post transplant (1–240 months). 14/44 subjects were treated with cytoreductive treatment following diagnosis of BCS and in 92.9% of these JAK2V617F was detected. 5/15 subjects went on to receive cytoreductive treatment following OLT of which all were JAK2V617F positive. We have found a high prevalence of JAK2V617F in patients with BCS. Latent MPD was missed in 12/25 subjects on BM morphology and 14/25 subjects on BM progenitor culture. We suggest that JAK2V617F analysis should be performed in all new cases of BCS. Given their age, these patients are possible candidates for JAK2 targeted therapy.

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